16-methyl-pregnane



Patented Dec. 25, 1952 3,070,614 l6-METHYL=PREGNANE Pietro De Ruggieri, Milan, ltaly, assignor to Urmonoterapia Richter S.p.A., Milan, Italy, a corporation of Italy No Drawing. Filed Mar. 7, 1961, Ser. No. 93,879 Claims priority, application Italy Apr. 22, 1960 2 Claims. (Cl. 260397.4)

An object of this invention is to provide a method for preparing compounds, which are useful intermediates in the synthesis of cortical hormones, represented by the following formula:

a (II-0A0 wherein R is hydrogen or oxygen and the bond between carbon atoms 5 and 6 is either a single or a double bond and, if single, the hydrogen in angular position 5 has a configuration. I

These compounds (Husler et al.: Helv. Chim. Acta, 42, 2043, 1959) when treated with bromine in presence of calcium oxide, give the 17a-bromo-derivatives in very good yield and free of contamination by poly-bromo compounds, which instead are obtained by traditional methods. By dehydrobrominating the l7a-bromo-derivatives in dimethylformamide with lithium bromide and lithium carbonate there are obtained the l6-methyl-pregn-l6-enes, which by hydrogenation with palladium over barium sulfate as catalyst are transformed into l6pmethyl-derivatives.

The following examples are given to further illustrate the products and process of the present invention and are not to be construed as limiting.

pregn-5,l7-(20)-diene in 200 parts of carbon tetrachloride was stirred at 5 C. with 2 parts of finely powdered calcium oxide and a solution of 7.8 parts of bromine in 40 parts of carbon tetrachloride was added dropwise for 5 minutes. After 10 minutes at 5 C. the mixture was filtered of calcium oxide and poured into a solution of 4.0 parts of sodium metabisulfite in 240 parts of water.

The organic layer was separated, washed with water and evaporated to dryness at reduced pressure.

This residue was dissolved in 400 parts of acetone, 40 parts of dry sodium iodide were added and the mixture was stirred at room temperature for one hour. The mixture was then diluted with 1600 parts of water and the product was filtered, washed with sodium hyposulfite 10% solution, water and dried in vacuum. Crystallization from methanol yielded 10.2-10.5 parts or" l6a-methyl-l7- a-bromo-pregn-5-one-3p-ol-20-one-3-acetate M.P. 172- 176 C.

Example 2.-16-Methyl-Pregna-5,16-Diene-3fl-Ol-20- One-S-Acetate A solution of 10 parts of 16a-methyl-17a-bromo-pregn- 5-ene-3p-ol-20-one-3-acetate in 200 parts of dry dimethyl formamide was heated for 3 hours at 100 C. in a nitrogen atmosphere, with parts of dry lithium bromide and 9.2 parts of dry lithium carbonate.

The lithium salts were filtered off and the solution diluted with 500 parts of water; the completely precipitated product was filtered, washed with water and dried in vacuum at 4050 C. A crystallization from methanol yielded 7.2-7.4 parts of 16-methyl-pregna-5,l6-diene- 3fl-ol-20-one-3-acetate M.P. 170-172" C.; [a] =93 (chi);

mm at 252 m log e=4.0

Example 3.16-Methyl-Pregna-5,1 6-Diene-313-Ol- ZO-One 0.5 part of 16-methyl-pregna-5,16-diene-3/8-ol-20-one- 3-acetate were refluxed for 1 hour with a solution of 0.625 part of potassium hydroxide in 25 parts of methanol; after dilution with water and filtration, the product was crystallized from acetone-hexane: M.P. 192193 C.; [a] =105 (chf.);

A at 250 my, log =4:.28

Example 4.16B-Methyl-Pregn-5-Ene-3p-Ol-20- One-.i-Acetate Example 5 .-1 6 fl-M ethyl-Pregn-5 -Eae-3p-0l-20-0ne A solution of 3 parts of l6-methyl-pregna-5,l6-diene- 3fi-ol-20-one in parts of ethyl acetate was shaken in a hydrogen atmosphere with 6 parts of a catalyst comprising 5% palladium absorbed on barium sulfate until no gas was further adsorbed, that is until saturation of 16,17-double bond. After separation of the catalyst by filtration, the solvent was driven ofi at reduced pressure and the residue was crystallized from methanol, yielding 2.6 parts of 16fi-methyl-pregn-5-ene-3,B-ol-ZO-one, M.P. 198-200 C.; [a] =--13 (diox.).

Example 6 .-1 6 a-M ethyl-1 7u-Bromo-5a-Pregnane- 3/8-Ol-20-One-3-Acemte A solution of 5.0 parts of l6a-methyl-35,20-diacetoxy- 5a-pregn-17(20)-ene in 100 parts of carbon tetrachloride was stirred at 5 C. with 1.0 part of finely powdered calcium oxide and a solution of 1.9 parts of bromine in 10 parts of carbon tetrachloride was added dropwise for 5 minutes.

After 10 minutes at 5 C. the mixture was filtered of the calcium oxide and poured into a solution of 1.0 part of sodium metabisulfite in 60 parts of water.

The organic layer was separated, washed with water and evaporated to dryness at reduced pressure; the residue was crystallized from methanol-acetone to give 5.2- 5.5 parts of 16u-methyl-17a-bromo-pregnane-3fi-ol-20- one-3-acetate, M.P. 138-142 C.

Example 7.-] 6-Methyl-5a-Pregn-1 6-Ene-3t3- Ol-20-One-3-A cetate A solution of 5.0 parts of 16a-methyl-l7tx-bromo-5apregnane-3 3-ol-20-one-3-acetate in 100 parts of dry dimethylformamide was heated for 3 hours at 100 C. in a nitrogen atmosphere with 5.3 parts of dry lithium bromide and 4.6 parts of dry lithium carbonate. The lithium salts were filtered off and the solution diluted with 250 parts of water; the completely precipitated product was filteerd, washed with water and dried in vacuum. Crystallization from methanol yielded 3.8-4.0 parts of 16-rnethyl-5m-pregn-16-ene-3 3-ol-20-one-3-acetate, M.P. 167-169 C.; [a] =23 (chf.);

A212? at 252 my, log :41)

Example 8.] 6 fi-M ethyl-5 a-Pregnane-3 Ol-20-One-3-A cetate A solution of 3.5 parts of 16-methy1-5a-pregn-16-ene- 3B-ol-20-one-3-acetate in 150 parts of ethyl acetate was shaken in hydrogen with 7.0 parts of a catalyst comprising 5% palladium adsorbed on barium sulfate catalyst until uptake of gas had ceased. After separation of catalyst through filtration, the solvent was removed at reduced pressure and the residue was crystallized from methanol to yield 3.0 parts of 16B-methy1-5a-pregnane- (chf.).

Example 9.-16a-Methyl-1 7a-Brom0-5a-Pr2gnane- 3 5 -01-1 1 ,2 O-Dion -3 -Acetate A solution of 10.0 parts of 16a-methyl-3fl,20-diacetoxy-a-pregn-17-(20)-ene-1l-one in 190 parts of carbon tetrachloride was stirred at 5 C. with 2.4 parts of finely powdered calcium oxide and over a period of 5 minutes a solution of 3.5 parts of bromine in 27 parts of carbon tetrachloride was added dropwise. After 10 minutes at 5% C. the mixture was filtered from calcium oxide and poured in a solution of 2.0 parts of sodium metabisulfite in 120 parts of water.

The organic layer was separated, Washed with water and evaporated to dryness at reduced pressure; the residue was crystallized from aqueous acetone yielding 10.2-10.5 parts of 16a-methyl-l7ot-bromo-5u-pregnane-Bfl-ol-11,20- dione-3-acetate, M.P. 169-171 C.

Example 10.--16-Methyl-5a-Pregn-16-Ene-3p-0l- 11,20-Di0ne-3-Acetate A solution of 10.0 parts of 16u-methyl-17a-bromo-5mpregnane-BB-ol-l1,20-dione-3-acetate in 170 parts of dry dimethylformamide was heated for 3 hours at 100 C. in a nitrogen atmosphere with 10.3 parts of anhydrous lithium bromide and 8.8 parts of anhydrous lithium carbonate. The lithium salts were filtered and the solution diluted with 650 parts of water. The completely precipitated product was filtered, Washed with water and dried in vacuum at 40-50 C. Upon crystallization from methanol there was obtained 6.8-7.0 parts of 16-methyl-5a- 4 pregn-16-ene-3f3-ol-1l,20dione-3-acetate, M.P. 165-167" C.; [a] :+24.3 (chf.);

5112. at 248 mp; log 6:4 0

Example 1] .16-Metlzyl-5a-Pregn-16-Ene- 3/8-0l-1L20-Di0ne 1.5 parts of 16-methyl-5wpregn-l6-ene-3B-ol-l1,20-dione-3-acetate were refluxed for 1 hour with a solution of 1.75 parts of potassium hydroxide in 70 parts of meth anol. After dilution with water and filtration, the product was crystallized from acetone to yield 1.2 parts of 16-methyl-5a-pregn-l6-ene-3,8-ol-11,20-dione, M.P. 223- 224 C.; [a] =-+43 (chf.);

A at 248 m log e=4.1

Example 12.16B-Methyl-5oc Pregnane-3/3 01-11 ,20- Dione-3-Acetate A solution of 3.5 parts of 16-methy1-5a-pregn-16-ene- 3/3-ol-11,20-dione-3-acetate in parts of ethyl acetate was shaken in a hydrogen atmosphere with 7.0 parts of a catalyst comprising 5% palladium adsorbed on barium sulfate until no more gas was absorbed. After separation of the catalyst by filtration, the solvent was driven off at reduced pressure and the residue was crystallized from methanol, yielding 3.1 parts of 16 3-methyl-5apregnane-SB-ol-l1,20-dione-3-acetate, M.P. -157 C.; [a] =-|-53 (chf.).

Example 13.1 6 fi-M eth yl-S a-Pregnane-3 B-Ol-l 1,20- Dione A solution of 1.2 parts of IG-methyl-Sa-pregn-16-ene- 3fi-ol-11,20-dione in 120 parts of ethyl acetate was shaken in a hydrogen atmosphere with 2.4 parts of a catalyst comprising 5% palladium adsorbed on barium sulfate until no more gas was adsorbed. After separation of the catalyst by filtration, the solvent was removed at reduced pressure, and the residue was crystallized from acetone-ethyl ether, yielding 1.1 parts of l6fl-methyl-5apregnane-3fl-ol-11,20-dione, M.P. 220-222 C.; [a];;: +70 (chi).

The present application is a continuation-in-part of my copending application Serial No. 39,433, filed June 29, 1960, and now abandoned.

I claim:

1. A method for the preparation of compounds of the formula wherein R is selected from the group consisting of Cz and C40 and X is selected from the group consisting of mo I 1.0L,

5 6 comprising the reaction of compounds of the formula wherein R is selected from the group consisting of CH c and 0 I c Ac 5 and X is selected from the group consisting of R ---cm i 5 and I MO k References Cited in the file of this patent X UNITED STATES PATENTS (m 2,684,963 Schock et al July 27, 1954 wherein R and X are the same as in Formula I, with 2,923,721 Joly et a1. Feb. 2, 1960 bromine in the presence of calcium oxide. 2,944,070 Kollonitsch et a1. July 5, 1960 2. A process as claimed in claim 1 comprising the 2,983,736 Georgian et a1 May 9,1961 additional step of reacting said compounds of Formula 2,989,553 Modderman et a1 June 20, 1961 I with lithium bromide and lithium carbonate in di- 3,013,034 Sletzinger et a1. Dec. 12, 1961 methylformsamide to form compounds of the formula FOREIGN PATENTS H 744,237 Great Britain Feb. 1, 1956 c=o OTHER REFERENCES Taub et al.: J. A. C. S. 80, 4435 (1958). 5 Loewenthal Tetrahedron 6, 269-303 (1959).

Taub et al.: J. A. C. S. 82, 4012-4026 (1960). 

1. A METHOD FOR THE PREPARATION OF COMPOUNDS OF THE FORMULA 